Methods for administering aripiprazole

ABSTRACT

The present invention relates, in part, to the discovery that a pharmaceutical composition comprising aripiprazole and a carrier administered in a bolus injection resulted in an extended release profile similar to that obtained by the injection of a poly lactide-co-glycolide microsphere formulation containing the active agent. This surprising result suggests that pharmacologically beneficial extended release formulations without the complexities and expense associated with the manufacture microspheres.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/648,544, filed Oct. 10, 2012 which is a continuation of U.S.application Ser. No. 12/251,656, filed Oct. 15, 2008, now U.S. Pat. No.8,338,427 issued Dec. 25, 2012, which is a continuation of U.S.application Ser. No. 10/635,221, filed Aug. 6, 2003, now abandoned. Theentire teachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Aripiprazole, sold under the tradename ABILIFY®, is a dopamine D₂ andserotonin 5-HT_(IA) receptor agonist and antagonist of the serotonin5-HT_(2A) receptor. Aripiprazole is used to treat schizophrenia andother psychotic and CNS disorders. See U.S. Pat. No. 5,006,528, forexample. ABILIFY®, is currently sold as a tablet for oraladministration. However, poor patient compliance with oralantipsychotics has been reported. As such, there exists a need forimproved methods of delivering antipsychotics, such as aripiprazole,thereby improving patient compliance and maximizing the pharmacologicalprofile of the active agent.

SUMMARY OF THE INVENTION

The present invention relates, in part, to the discovery that apharmaceutical composition comprising aripiprazole and a carrieradministered in a bolus injection resulted in an extended releaseprofile similar to that obtained by the injection of a polylactide-co-glycolide microsphere formulation containing the activeagent. This surprising result suggests that pharmacologically beneficialextended release formulations without the complexities and expenseassociated with the manufacture of polymeric microspheres can beachieved.

Thus, the invention relates to an injectable composition for theextended release of aripiprazole comprising injecting or implanting acomposition comprising aripiprazole wherein aripiprazole is present inthe serum of the mammal for at least about 7 days, preferably at leastabout 14 days, more preferably at least about 21 days, such as aboutthree months. In a preferred embodiment, the composition comprises asuspension of aripiprazole in an injection vehicle, such as a suspensionof an aripiprazole drug substance in an injection vehicle. Thearipiprazole drug substance can comprise, consist essentially of orconsist of aripiprazole (in a crystalline, non-crystalline or amorphousform), an aripiprazole salt, an aripiprazole solvate (includinghydrates), or other aripiprazole polymorphs. The aripiprazole, oraripiprazole drug substance, can be added in a specified size. Forexample, the aripiprazole or aripiprazole drug substance can be addedafter being micronized to a mass mean diameter of less than about 100microns, preferably between about 30 and 80 microns, as determined byCoulter counter.

In one embodiment, the aripiprazole or aripiprazole drug substance isinjected as a mixture (including a suspension) of at least about 50 mgaripiprazole in an injection vehicle, such as at least about 70 to 210mg or as much as about 900 to 2700 mg, e.g. less than 5400 mg. Thearipiprazole can be present in an amount of at least about 10 mg/ml,preferably at least about 20 mg/ml or at least about 30 mg/ml. Theinvention also relates to methods for providing aripiprazole to anindividual in an extended release injectable composition comprisingadministering a mixture of at least about 10 mg/ml aripiprazole in aninjection vehicle comprising a viscosity enhancing agent and tocompositions useful in such methods.

BRIEF DESCRIPTION OF THE DRAWINGS

The FIGURE compares the release profiles of subcutaneous injections (SCBolus) according to the invention with injections ofaripiprazole-containing microspheres.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to an injectable composition for the extendedrelease of aripiprazole comprising a mixture of aripiprazole in aninjection vehicle comprising an optional viscosity enhancing agent. Thearipiprazole can be present in an amount of at least about 10 mg/ml,preferably at least about 20 mg/ml or at least about 30 mg/ml. Theinvention also relates to methods for providing aripiprazole to anindividual in an extended release injectable composition comprisingadministering a mixture of at least about 50 mg aripiprazole in aninjection vehicle.

In general, the aripiprazole will be suspended in the injection vehicle.In one embodiment, the aripiprazole is supplied in a free flowingpowder, substantially free of major amounts of pharmaceutical excipientsor other compounds. For example, the aripiprazole can be supplied in amicronized state, consisting of or consisting essentially ofaripiprazole. An aripiprazole drug substance can be said to consistessentially of aripiprazole if it contains, for example, 90% by weightor more aripiprazole and minor amounts (e.g., less than 10% by weight)of other materials that are, for example, residual to its process formanufacture. Compounds that may be found in a substantially purearipiprazole drug substance can include wetting agents used, forexample, to facilitate micronization, grinding or comminution, residualsolvents, reaction by products or staring materials.

The compositions of the present invention are free of sustained releasematrices. Sustained release matrices are polymers and othermacromolecules (albumin), present in major amounts (e.g., 50% by weightor more of total solids), which when the active agent is dispersedtherein, are used to slow the exposure or bioavailability of the activeagent in the patient. A frequently used polymeric matrix is polylactide-co-glycolide polymers. Thus, the aripiprazole drug substanceand/or injectable compositions of the invention generally do not containmajor amounts of PLGA polymer matrices.

Of course, polymers are often found in pharmaceutical compositions wherethe activity is not at all related to extending the release profile ofthe drug. For example, minor amounts of polysorbates, polyamines,polyvinylalcohol and polyethylene glycols are added to facilitatedispersibility of active agents in its vehicles. The inclusion of suchpolymers in amounts intended to accomplish these functions, and inamounts that do not permit the formation of substantial matrixformation, is permitted.

The aripiprazole drug substance is added to an injection vehicle. Thedrug substance can be dispersed or suspended in the vehicle, dependingupon the solubility of the drug in the vehicle. The vehicle ispreferably an aqueous vehicle which suspends the drug substance.Preferably, the vehicle contains a viscosity enhancing agent.

Viscous vehicles can have, for example, a viscosity of at least 20 cp at20° C. In other embodiments, the fluid phase of the suspension has aviscosity at 20° C. of at least about 30 cp, 40 cp, 50 cp, and 60 cp arepreferred. The viscosity can be achieved by adding a viscosity enhancingagent, such as a carboxymethyl cellulose, such as sodium carboxymethylcellulose. In one embodiment, the injection vehicle comprises atleast about 1% by volume sodium carboxymethyl cellulose, preferablyabout 3% by volume carboxymethyl cellulose.

The injection vehicle can advantageously contain a wetting agent, suchas a polysorbate. Suitable polysorbates include polysorbate 20,polysorbate 40, and polysorbate 80, sold under the trademark TWEEN®. Thewetting agent can be added in an amount that enhances the dispersibilityof the active agent. An example of a suitable amount includes about 0.1to 2% by weight of polysorbate 20.

The injection vehicle can also advantageously employ a density enhancingagent, such as a sugars, e.g. mannitol, or sorbitol and/or a tonicityadjusting agent, such as sodium chloride. In one embodiment, thetonicity adjusting agent is about 1% by weight, including 0.9% byweight.

In one embodiment, the composition consists of the aripiprazole drugsubstance and the injection vehicle, thereby providing a surprisinglysimple and elegant formulation for obtaining an extended or sustainedrelease profile.

The aripiprazole drug substance can comprise, consist essentially of orconsist of aripiprazole (in a crystalline, non-crystalline or amorphousform), an aripiprazole salt, an aripiprazole solvate (includingethanolates and hydrates), or other aripiprazole polymorphs. Preferredsalts include those salts insoluble in an aqueous vehicle.Pharmaceutical salts such as the hydrochloride and hydrobromide saltsare suitable.

The methods of the invention include administering the compositionsdescribed herein, thereby obtaining an extended release or sustainedrelease profile in the patient. An extended release profile includesdeliveries that achieve a therapeutically effective amount of thearipiprazole is present in the plasma of the individual for at leastabout 7 days, preferably at least about 14 days, or more preferably atleast about 21 days alternatively for at least 2, 3, 4, 6 or 8 weeks oras much as three months.

In one embodiment, the formulations can be administered as a single orsole dose. However, the invention is particularly beneficial for thoseindividuals that require constant or chronic therapy, such as those thatreceive repeated doses over several weeks or months or more. In suchdosing regimens, the method can comprise a first administration of afirst extended release formulation and a second administration of asecond extended release formulation. The second formulation can be thesame, substantially the same or different as the first and can includethe same active agent or a different active agent. For example, thesecond formulation can be administered at about 7 days, or more, such asat least about 14 days, or at least about 17 days, after the firstadministration, where the first administration results in the release ofagent for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14days, or more.

The term “therapeutically effective amount” is further meant to definean amount resulting in the improvement of any parameters or clinicalsymptoms. The actual dose may vary with each patient and does notnecessarily indicate a total elimination of all disease symptoms.

As used herein, the term “individual”, “subject” or “patient” refers toa warm blooded animal, including but not limited to humans, such as amammal which is afflicted with a particular disease state.

A therapeutically effective amount of the compound used in the treatmentdescribed herein can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining the therapeutically effective dose, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The mode of administration will generally be by injection orimplantation, such as intramuscularly or subcutaneously.

Preferred amounts according to the selected mode of administration areable to be determined by one skilled in the art. Pharmaceuticalcompositions can be manufactured utilizing techniques known in the art.Typically the therapeutically effective amount of the compound will beadmixed with a pharmaceutically acceptable carrier.

For injection, the compounds may be in a physiologically acceptablepharmaceutical carrier and administered as a suspension. Illustrativepharmaceutical carriers also include water, aqueous methylcellulosesolutions, saline, dextrose solutions, fructose solutions, ethanol, oroils of animal, vegetative, or synthetic origin. The pharmaceuticalcarrier may also contain preservatives, and buffers as are known in theart.

When the composition is to be used as an injectable material, includingbut not limited to needle-less injection, it can be formulated into aconventional injectable carrier. Suitable carriers include biocompatibleand pharmaceutically acceptable solutions.

In a preferred embodiment, the size of the drug particle can becontrolled. Often, the mass mean diameter of the drug particles is lessthan 100 microns, such as between about 1 and 100 microns, preferablyabout 10 and 100 microns, or about 20 and 60 microns.

In one embodiment, the unit dosage form can be stored as a dry powder,for example, to be mixed for injection prior to use, or as a stablesuspension ready for use. Other methods for storing or administrationusing art recognized methods are also contemplated herein.

Experimental: Pharmacokinetic Evaluation of Aripiprazole in RatsFollowing Administration of Single Subcutaneous Doses of AripiprazoleFormulations Species and Strain:

-   -   Sprague-Dawley rats. Male; 450+/−50 grams.

Study Groups: 5 Groups, 15 Subjects

-   -   Group A: three rats injected once SC with 10 mg of Aripiprazole.    -   Group B: three rats injected once SC with 20 mg of Aripiprazole.    -   Group C: three rats injected once SC with 30 mg of Aripiprazole.    -   Group D: three rats injected once SC with ˜67 mg of        microparticles.    -   Group E: three rats injected once SC with ˜40 mg of        microparticles.

Group Conditions Table:

Rat Groups Lot # Polymer Notes % Load A N/A Bulk Drug 100% B N/A BulkDrug 100% C N/A Bulk Drug 100% D 03-10-66-B 4A Bulk Drug in  30%microspheres E 03-10-66-C 4A Bulk Drug in  50% microspheres

Route of Injection:

-   -   Subcutaneous (SC) injection into the interscapular region.

Injection Vehicle:

-   -   Aqueous diluent containing 3% CMC (low viscosity), 0.1% Tween        20, in 0.9% NaCl and water.

Dose Volumes:

-   -   Suspensions were formulated as follows:    -   Group A: 10 mg powder in 0.75 mL Diluent    -   Group B: 20 mg powder in 0.75 mL Diluent    -   Group C: 30 mg powder in 0.75 mL Diluent    -   Group D: ˜67 mg microparticles in 0.75 mL Diluent    -   Group E: 40 mg microparticles in 0.75 mL Diluent

Blood Collection:

-   -   Blood samples were collected via a lateral tail vein after        anesthesia with Halothane. A syringe without an anticoagulant        was used for the blood collection, then the whole blood was        transferred to tubes containing K2 EDTA and mixing beads        (MICROTAINER®; MFG# BD365974). The blood samples were processed        (the tubes are inverted 15-20 times and centrifuged for 2        minutes at >14,000 g's) to separate plasma. The plasma samples        prepared in this manner were transferred to labeled plain tubes        (MICROTAINER®; MFG# BD5962) and stored frozen at <−70° C.

Blood Volumes:

-   -   At least 250 μL blood were collected at for each time point        during the first 24 hours and 400 μL for at each time point        thereafter.

Time Points to Obtain Plasma:

2 h 24 h 3 d 10 d 21 d 4 h 32 h 4 d 14 d 24 d 8 h 2 d 7 d 17 d 28 dNote: when plasma concentration was lower than the limitation ofquantification, that group of rats were terminated.

The results obtained are reported in the FIGURE. Surprisingly, the ratsthat received bolus injections of aripiprazole and injection vehiclealone were substantially the same as those that received thearipiprazole dispersed within a PLGA microsphere.

Modifications and variations of the invention will be obvious to thoseskilled in the art from the foregoing detailed description of theinvention. Such modifications and variations are intended to come withinthe scope of the appended claims.

All patents, patent application publications and articles cited hereinare incorporated by reference in their entirety.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1.-23. (canceled)
 24. An injectable composition comprising a suspensionof at least about 10 mg/ml of aripiprazole in an injection vehiclecomprising water, carboxymethyl cellulose or sodium carboxymethylcellulose, wherein the injectable composition is free of sustainedrelease materials for the extended release of aripiprazole, and thearipiprazole release is for at least 7 days.
 25. The composition ofclaim 24, wherein said injection vehicle further comprises a wettingagent.
 26. The composition of claim 25, wherein said wetting agent ischosen from polysorbate 20, polysorbate 40, and polysorbate
 80. 27. Thecomposition of claim 24, wherein said injection vehicle furthercomprises a density enhancing agent.
 28. The composition of claim 27,wherein said density enhancing agent comprises sorbitol.
 29. Thecomposition of claim 24, wherein said injection vehicle furthercomprises a tonicity adjusting agent.
 30. The composition of claim 29,wherein said tonicity adjusting agent comprises sodium chloride.
 31. Amethod for providing aripiprazole to an individual in an injectablecomposition comprising a suspension of at least about 10 mg/ml ofaripiprazole in an injection vehicle comprising water, carboxymethylcellulose or sodium carboxy methylcellulose, wherein the injectablecomposition is free of sustained release materials for the extendedrelease of aripiprazole, and the aripiprazole release is for at least 7days.
 32. The method of claim 31, wherein said injection vehicle furthercomprises a wetting agent.
 33. The method of claim 32, wherein saidwetting agent is chosen from polysorbate 20, polysorbate 40, andpolysorbate
 80. 34. The method of claim 31, wherein said injectionvehicle further comprises a density enhancing agent.
 35. The method ofclaim 34, wherein said density enhancing agent comprises sorbitol. 36.The method of claim 31, wherein said injection vehicle further comprisesa tonicity adjusting agent.
 37. The method of claim 36, wherein saidtonicity adjusting agent comprises sodium chloride.
 38. The method ofclaim 31, wherein the composition is administered by injection chosenfrom intramuscular injection and subcutaneous injection.
 39. The methodof claim 31, further comprising a second administration of thecomposition chosen from at least about 7 days after first administrationand at least about 14 days after the first administration.
 40. Acomposition comprising a suspension of at least 50 mg of aripiprazoleand an aqueous injection vehicle comprising water;carboxymethylcellulose or sodium carboxy methylcellulose; a wettingagent; and a tonicity agent; wherein the composition is free ofsustained release materials; wherein the concentration of aripiprazolein the composition is at least 20 mg/ml; and wherein upon injection ofthe composition into an individual, the aripiprazole is present in theplasma of the individual for about 7 days or more.